Many active ingredients which are recognized as beneficial for to improving skin or hair condition and feeling, for reducing signs of aging and photoaging or for the treatment of skin disorders such as acne, psoriasis, seborrhea and infections, are difficult to formulate in cosmetic compositions or in pharmaceutical preparations. Often these active ingredients decompose when in contact with water, oxygen, oxidants, trace amounts of metallic ions, or with components commonly used in cosmetic or dermatological compositions. Consequently, the shelf life of products containing these ingredients is reduced. Another prevalent problem is that while being effective in treating the skin, many of these active ingredients cause skin irritation. A delivery system for sustained release can contribute to decreasing such irritation by reducing the concentration of active ingredients that are in contact with the skin or hair, at any given moment. In addition, sustained release can extend the duration of activity of the ingredient.
Perfumes are an example of an ingredient that is frequently added to pharmaceutical, cosmetic or cosmeceutic compositions. Perfumes, while having no therapeutic action, often cause skin irritation. Entrapment of perfumes may serve to decrease skin sensitivity to perfumes, while extending their period of effectiveness through the mechanism of sustained release. Colors and dyes can also benefit from entrapment, since they are often incompatible with other formulation ingredients.
Various formulations have been developed to address these problems. Improved emulsions of water-in-oil or oil-in-water have been developed, such as that described in U.S. Pat. No. 6,171,600, which discloses use of a double emulsion, U.S. Pat. No. 5,851,538 discloses a protection system based on the adsorption of the active ingredient in pores that are present in an organic polymer in a sponge form, U.S. Pat. No. 3,957,971 and U.S. Pat. No. 5,874,105 utilize liposomes as a delivery system.
U.S. Pat. No. 6,103,267 and U.S. Pat. No. 6,146,664 show that sensitive active ingredients, such as Vitamin A and Vitamin C, can be stabilized as dispersions in a non-solvent and still be active when applied on the skin. A similar approach was used in U.S. Pat. No. 6,077,522, for stabilizing biologically active compounds for various uses.
FR 2780901, WO 99/03450. FR 2703927, WO 94/04260 and WO 94/04261 disclose microparticles and nanoparticles for encapsulation of cosmetics, pharmaceutics and food compositions, which include cell walls that are formed by cross-linking of organic and bio-organic polymers.
All the formulations described hereinabove employ organic or, bio-organic matrices for stabilizing the active ingredients prior to their use. Organic polymers are inherently more susceptible to chemical and photochemical damage as compared with inorganic polymers. In addition, organic and bio-organic matrices are highly sensitive to shear forces, osmotic pressure, heat, etc., and therefore, tend to release substantially the entire content of active ingredients contained therein immediately following to application, hence failing to provide controlled stabilization and delivery.
Another ingredient that is frequently added to pharmaceutical, cosmetic or cosmeceutic compositions, particularly to anti-acne and dental compositions, is benzoyl peroxide. Such compositions often include a combination of benzoyl peroxide, as a dispersion, and other active ingredients, such as retinoids and antibiotics, which typically exert a synergistic effect in the treatment of acne and other skin or dental conditions, diseases and disorders. However, the preparation and use of these compositions is limited since benzoyl peroxide is a highly reactive oxidation agent and therefore oxidizes the additional active ingredients. Therefore, the presently known formulations that include benzoyl peroxide are typically characterized by limited stability and short shelf life, hence, separate containers are often used for each of the active ingredients.
U.S. Pat. No. 6,013,637 discloses an anti-acne composition which includes benzoyl peroxide and lycomycin. The disclosed composition is stable for one month. Indeed, this patent further discloses an end product which includes separate kits for the benzoyl peroxide and the antibiotic agent U.S. Pat. No. 4,350,681 discloses a method of stabilizing benzoyl peroxide in a dispersion and a method of treating acne using a benzoyl peroxide composition and a retinoic acid composition. Indeed, the method disclosed in this patent comprises separate topical application of the compositions at a time interval of 10 minutes.
Hence, the prior art fails to teach a delivery system that provides protection of naive active ingredients from benzoyl peroxide and/or other harsh substances prior to their application. The prior art also fails to disclose a stabilizing system designed to release the active ingredients upon topical application.
Another media for controlled delivery of drugs, which can be utilized to protect sensitive ingredients, is doping within sol-gel matrices. In this method, monoliths, particles or other forms (such as thin layers, or fibers) are prepared, and the active ingredient is immobilized in the pores of the sol-gel matrix. The sol-gel matrix is doped with small amounts of the active ingredient. This method is utilized in U.S. Pat. No. 5,591,453, WO 97/45367, U.S. Pat. No. 4,169,699. DE 19811900. WO 00/47236, U.S. Pat. No. 4,988,744. JP 07173452. WO 01/12221. JP 09110463 WO 01/13924 and EP 281034, and is further disclosed in Goto et al., Nanoparticles Res. 1 (1999), 205 and in Vallet-Regi et al., Chem. Mater. 13 (2001), 308.
However, sol-gel doped matrices cannot support high loading (of up to 95% wt.) of the active ingredient. In order to obtain high loading, it is essential to form a core-shell structure, where most of the weight of the capsule is the weight of the encapsulated active ingredient (core), and where the thin shell protects the core effectively, U.S. patent application Ser. No. 09/372,176 discloses a method for the preparation of silica microcapsules containing organic compounds for various uses. This method was utilized in the development of encapsulated sunscreen active ingredients, disclosed in U.S. Pat. No. 6,238,650; where active ingredients are highly retained within the silica capsules, minimizing exposure of the skin to the active ingredient. Sol-gel microcapsules of silica, when formed according to U.S. patent application Ser. No. 09/372,176, are chemically and photochemically stable, inert and safe for use. When incorporated in cosmetic or pharmaceutical compositions they afford a transparent, cosmetically pleasing product. The hydrophobic/hydrophilic character of the capsules is tailored to suit the purpose, by selecting appropriate sol-gel precursors and reaction conditions. Selection of the makeup of the microcapsule precursors, determines the character of the microcapsular shell surrounding the active ingredient. Thus, for instance, hydrophobicity/hydrophilicity can be controlled, so that water-soluble actives and oil-soluble actives can both be present in the same formulation, by encapsulation of one or the other. It is possible to encapsulate hydrophobic materials, that would have required the presence of large quantities of oils in the formulation, in silica, which has a hydrophilic extetrnal surface, allowing easy incorporation into aqueous phases. Generally, water based products or emulsions such as oil-in-water emulsions with external water phase are considered to afford improved feel on the skin, and are therefore preferred in many cases over oil-based products (ointments) or water-in-oil emulsions. For that reason it is desirable to have a delivery system that is water dispersible, to allow easy incorporation in the water phase.
Thus, U.S. patent application Ser. No. 09/372,176 and U.S. Pat. No. 6,238,650 (both incorporated herein by reference) disclose microcapsule formulations specifically designed to prevent an encapsulated active ingredient from leaving the microcapsule. This is desirable when the active ingredient is an irritant to the body tissue to which it is applied. It is also desired when the active ingredient acts by interaction with light, such as sunlight. However, U.S. patent application Ser. No. 09/372,176 and U.S. Pat. No. 6,238,650 fail to disclose compositions and methods for releasing and hence delivering the active ingredients.
Thus, a system that is capable of both holding and protecting the sensitive active ingredient in the formulation and of releasing and hence delivering the active ingredient upon application is not disclosed by the prior art. Such a system can serve to shield and protect active ingredients from undesired decomposition, thus extending the shelf life of the composition and may also serve to segregate incompatible agents present in the same composition during storage. Furthermore, the activity of the active ingredients can be optimized as a result of sustained release, while skin irritation can be reduced, since there is a significant reduction in the concentration of active ingredient in direct contact with the skin, at any given time.
There is thus a widely recognized need for, and it would be highly advantageous to have compositions for topical application that include therapeutic, cosmetic or cosmeceutic active ingredients encapsulated in sol-gel microcapsules, which are designed to stabilize and deliver the active ingredients encapsulated therein.